This K23 award application describes a career development plan for Dr. Brian Vickery, an Instructor in the Division of Pediatric Allergy and Immunology at Duke University Medical Center. This award will provide Dr. Vickery with the necessary support and training to develop into an independent physician-investigator specializing in allergic disorders of childhood. Specifically, the award will enable Dr. Vickery to accomplish the following goals: (1) to master skills necessary to design and execute clinical trials; (2) to become proficient in advanced biostatistical skills suitable for analysis of longituinal studies; (3) to develop expertise in mechanistic immune monitoring assays; and (4) to achieve an independent research career conducting high-impact patient- oriented research focusing on immune tolerance-based therapies for allergic disorders. To accomplish these goals, Dr. Vickery has assembled a mentorship advisory committee led by Dr. Wesley Burks, an international expert in food allergy and immunological tolerance. Dr. Burks will lead a team of other renowned investigators with extensive mentorship experience, whose scientific interests collectively include basic and translational immunology, pediatric pharmacology, and clinical trials. Dr. Vickery will complement this intensive career development guidance with advanced didactic coursework in biostatistics, research design, pharmacology, and advanced laboratory methods. Peanut allergy is a severe and potentially fatal immunologic problem affecting approximately 1% of children in the U.S. and other developed nations. Without an effective disease-modifying therapy, patients suffer significant physical and psychological morbidity, including the profound reduction in quality of life that results from an ever-present risk of life-threatening anaphylaxis Based on recent studies highlighting the potential plasticity of allergic responses early in life, and the role of oral exposure during this critical period, we have designed a single-center randomized clinical trial to test early intervention with low-dose and high-dose peanut oral immunotherapy (OIT) in 40 newly diagnosed peanut-allergic children aged 9 - 36 months. The goals of this project are: to produce a new treatment that would rapidly benefit peanut-allergic subjects, by transiently altering reactivity and lowering the risk of anaphylaxis while on treatmen (i.e., desensitization) (Aim I); to assess the ability of this treatment to permanently alter the peanut-specific immune response over time, allowing discontinuation of therapy (i.e., tolerance) (Aim I); and to understand its mechanism of action (Aim II). While providing a mentored training experience in clinical research, this innovative trial focuses directly on several critical knowlede gaps that must be addressed in order to develop the first clinically available food allergy treatment and change the standard of care. PUBLIC HEALTH RELEVANCE: The outcome of this work has the potential to change the way peanut allergy is treated, by developing a safe, inexpensive, feasible, and effective disease-modifying therapy that could be made immediately available to infants and toddlers. This project will study early intervention with peanut oral immunotherapy in young children, generate important new scientific knowledge of immunologic tolerance in humans, and examine the impact of treatment on health-related quality of life.